Although considered strictly inaccessible to all but a few investigators, variola major remains a potentially devastating bioterrorist threat. The underlying mechanisms of poxvirus pathogenesis are only partially understood, but have been studied intensively in the non-human primate aerosol model of monkeypoxvirus (MPXV). In this model, cynomolgus macaques are exposed to a high-dose, small particle, which is inhaled into the lungs and reaches the alveoli. In contrast, large particle aerosol exposure generally deposits in the nasal cavity or oropharynx, and eventually migrates to back of the throat and is swallowed. Little is known about the mechanism of large particle aerosol poxvirus pathogenesis. Since the aerosol route is the major natural route of transmission for smallpox, and is the likely route for intentional dispersal, and because casual contact with aerosols (through talking, coughing, and sneezing) can create both large and small particle aerosols, it is very important to determine the role of both particle sizes in the transmission of smallpox.